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Review article

Targeting the inflammatory component of schizophrenia

Explorando o componente inflamatrio da esquizofrenia
Hassan Rahmoune1, Laura W. Harris1, Paul C. Guest1, Sabine Bahn1,2

Department of Chemical Engineering and Biotechnology, University of Cambridge, Tennis Court Road, Cambridge, UK.
Department of Neuroscience, Erasmus Medical centre, Rotterdam, The Netherlands.

Received: 9/23/2012 - Accepted: 11/7/2012

Schizophrenia is a heterogeneous disease characterised by an array of clinical manifestations. A large number of studies over the last 20 years have pointed towards
immune system abnormalities in patients suffering from this condition. In addition, the psychosis and cognitive dysfunction associated with schizophrenia have
been shown to be linked with autoimmune diseases. Here, we review the evidence, which suggests that a pro-inflammatory status of the immune system induces
psychopathologic symptoms and may be involved in the pathophysiology of this major mental illness. We also propose that future preclinical and clinical stu
dies should take such pre-defined causes and the dynamic status of the inflammatory component into account. Patient stratification and personalised medicine
strategies based on targeting the inflammatory component of the disease could help in alleviation of symptoms and slowing disease progression. Ultimately, this
could also lead to novel concepts in schizophrenia target/molecular identification and drug discovery strategies.
Rahmoune H, et al. / Rev Psiq Cln. 2013;40(1):28-34
Keywords: Schizophrenia, inflammation, immune system, biomarkers.

A esquizofrenia uma doena heterognea caracterizada por um conjunto de manifestaes clnicas. Um grande nmero de estudos ao longo dos ltimos 20 anos
apontou para anormalidades no sistema imune em pacientes que sofrem dessa condio. Em adio, tem sido mostrado que a psicose e a disfuno cognitiva
associadas com a esquizofrenia esto ligadas a doenas autoimunes. Aqui, revisamos a evidncia que sugere que um status pr-inflamatrio do sistema imune
induz sintomas psicopatolgicos e pode estar envolvido na fisiopatologia dessa principal doena mental. Tambm propomos que futuros estudos pr-clnicos e
clnicos deveriam levar em conta tais causas predefinidas e o status do componente inflamatrio. Estratificao de pacientes e estratgias de medicina personali
zadas baseadas no direcionamento ao componente inflamatrio da doena poderiam ajudar na reduo de sintomas e da progresso da doena. Por fim, isso
poderia levar a novos conceitos na identificao de alvos moleculares em esquizofrenia e estratgias de descoberta de drogas.
Rahmoune H, et al. / Rev Psiq Cln. 2013;40(1):28-34
Palavras-chave: Esquizofrenia, inflamao, sistema imune, biomarcadores.

Schizophrenia is a complex psychiatric disorder which affects approximately 1% of the world population. Although considerable progress
has been made in the search for contributing factors, the aetiology
of the disease is still far from understood. Heterogeneity throughout
the onset and progression of schizophrenia is a major factor slowing
down scientific progress in the field. Another complicating factor is
the overlap of symptoms with other psychiatric and neurological
disorders and it remains unclear whether the different manifestations reflect subtypes with different aetiologies or whether diverse
clinical syndromes may have overlapping pathologies. These factors
have led to a high rate of misdiagnosis using the current subjective
clinical rating systems1. For this reason, there is now intensive effort
to identify more empirical measures based on molecular fingerprints
underpinning the disease aetiology. One problem is the need to
identify peripheral biomarkers which can be measured easily in the
clinic. Previously the main focus of schizophrenia research has been
to identify pathophysiological changes in the brain, a biomaterial
which is largely unavailable to the clinician for diagnostic purposes.
Thus aspects of the disorder that are reflected in peripheral tissues
are an important focus for biomarker discovery.
Here, we review the advances made in elucidating the potential
role of the immunological component of schizophrenia. There has
been considerable evidence indicating the significance of neuroin-

flammation and immunogenetics in schizophrenia2. This has been

characterized by an increased serum concentration of several pro-inflammatory cytokines. The brain physiological interactions between
the brain and immune systems have also been well established3,4. In
response to environmental insults, subjects with schizophrenia can
develop a compromised immune system5.
There is also a genetic contribution to schizophrenia with estimates of heritability ranging from 30% to 85%4,6. However, the exact
genetics of these disorders are far from being elucidated. Previous
studies suggest that several genetic, endogenous and environmental
factors are involved and these may interact to bring about specific
disease manifestations7. The precise interaction between the genetic
vulnerability to develop schizophrenia and environmental factors
is still unclear. However, linkage and association studies have been
conducted in an attempt to identify candidate susceptibility genes
for schizophrenia and other psychiatric disorders8. Genetic studies
have identified an association of polymorphisms related to inflammation. The interleukin 1 (IL-1) gene cluster in schizophrenia was
suggested recently9. However, the increased risk of developing the
disorder is unlikely to be accounted for by a single gene and is most
probably a combination of several different genes. For even the most
promising gene polymorphisms such as neuregulin-1, the additional
risk is low at approximately 2% instead of the 1% risk seen in the
general population10.

Address correspondence to: Hassan Rahmoune. University of Cambridge, Tennis Court Road, Cambridge. CB2 1QT, UK. Telephone: +44 1223 334 151 Fax: +44 1223 334 162. E-mail:

Rahmoune H, et al. / Rev Psiq Cln. 2013;40(1):28-34

Brain studies
The pro-inflammatory status associated with neuropsychiatric diseases has been extensively investigated and well established11.The
activation of the brain immune system has been suggested by the
increased levels of IL-1 in the cerebrospinal fluid in first-episode
schizophrenia patients12. Brain development is also known to be
regulated by pro-inflammatory agents13,14. Maternal infection in
pregnancy can increase the risk of developing schizophrenia by impacting the neuro-developmental stage in the foetus. This is due to
the fact that the balance between pro and anti-inflammatory agents
may influence brain development and behaviour15.
Transcriptomic profiling of post-mortem brain or peripheral
tissues can provide useful insights into the perturbed biological
processes in central nervous system disorders. The gene expression
level of pro-inflammatory cytokines in preclinical models of schizophrenia and human subjects have been shown to be increased in the
prefrontal cortex region of the brain16. Several transcriptomic studies
have shown that inflammation-related genes which are increased
in schizophrenia brains are also associated with oligodendrocyte
and endothelial cells. In these cells, transcription can be induced by
the inflammatory cytokines tumour necrosis factor alpha (TNF-),
interferon alpha (IFN-) and interferon gamma (IFN)-17-19. Ho
wever, these effects are likely to be confounded by antipsychotic
drug-treatment, poor diet or unhealthy life styles, which are often
associated with chronic stages of the disease15.
The availability of tissues which are more accessible is necessary
to apply these approaches clinically. A recent study carried out data
analysis from the transcriptomic profiling of 33,698 genes in 79
human tissues20. The results suggested that while whole blood cells
share significant gene expression similarities with central nervous
system tissues, the correlation between transcripts present in both
of these was around 0.5, which was less than immune tissues (0.64)
and comparable to a somatic tissues (0.57). The authors concluded
that gene expression in whole blood cells is only partially correlated
with that seen in brain tissues.
There are also numerous reports of immune abnormalities in
the central nervous system and in the periphery of patients with
schizophrenia21-23. Cytokine levels have been measured in brain and
body fluids such as cerebrospinal fluid (CSF) and blood serum of
patients with schizophrenia and a decreased inflammation response
has been linked with decreased production of T helper (Th)-1 cytokines24. The pituitary gland is known to be involved in regulation
of the central nervous system and peripheral tissues by release of
hormones involved in vital body functions. Thus, the pituitary provides a regulatory link between the blood and brain. Furthermore,
the pituitary is controlled by inflammatory stimuli, as the production
of adrenocorticotrophic hormone (ACTH), growth hormone (GH)
and thyroid stimulating hormone (TSH) appears to be regulated by
IL-625. One of the first direct evidence reflecting a pro-inflammatory
status in the brain at the disease onset was provided by Van Berckel
et al.26. Using PET imaging techniques Van Berckel et al. have shown
microglial activation in the brain of schizophrenic patients within the
first five years of the disease onset. Further pre and clinical studies are
needed to unravel the causality of blood and brain pro-inflammatory
status in neuropsychiatric diseases such as schizophrenia. Nevertheless, in the past decades scientists has stipulated that infectious agents
(e.g. herpes simplex virus, Epstein-Barr virus and toxoplasma) as a
possible cause of schizophrenia27 and such a phenomenon may be
explained by chronic infections or compromised immune status.
Finally, a large set of data have also stipulated that environmental
factors such as oxidative stress plays a major role causing or exaggerating the inflammatory component of schizophrenia28.

Peripheral studies
Inflammation has been associated with schizophrenia for decades
and studies of changes in inflammatory molecules may lead to a
means of patient stratification prior to antipsychotic treatment29.


A previous study which carried out a meta-analysis revealed alterations in cytokines in blood and cerebrospinal fluid from patients
with schizophrenia30. Numerous studies have reported that circulatory and cellular pro-inflammatory alterations are associated with
schizophrenia31. Analysis of the transcriptome pattern in circulating
monocytes isolated from patients suffering from schizophrenia and
bipolar disorder showed a pro-inflammatory status associated with
monocyte and T-cell activations32. However, some of these studies
have provided an inconsistent picture, which is most likely due to
differences in the number or type of cytokines measured33,34 or the
presence of confounding factors such as different disease subtypes,
co-morbidities, illness duration and the fact that patients had been
treated with antipsychotics. In addition, many of these studies have
been performed using peripheral blood mononuclear cells (PBMC)
which may have led to inconsistencies related to differences in the
isolation procedures used. The macrophage-T cell theory of depression and schizophrenia35 postulates an aberrant inflammatory
state of monocytes, macrophages and T cells in patients with mood
disorders or schizophrenia is contributing to the illness. Aberrant
levels of inflammatory cytokines can destabilize function of the brain
and the hypothalamic-pituitary-adrenal (HPA) axis, which can lead
to changes in mood and behaviour. Most studies have focused on
serum levels of neopterine or other cytokines in targeted approaches
and these demonstrated the presence of an aberrant inflammatory
state in psychiatric patients. However, this has led to inconsistent
results as single determinations are not precise or robust enough to
consistently measure alterations in immune function.
In a study aimed at identifying proteomic signatures and molecular pathways underlying schizophrenia, we carried out multiplex
immunoassay analyses of serum samples from first-episode, drug
naive schizophrenia patients which resulted in identification of
a disease signature36. Interestingly, many of these molecules have
been implicated previously in patients with auto-immune37,38 or
metabolic diseases39. Further study of these pathways may result in
important breakthroughs in schizophrenia research as this could
lead to a means of stratifying patients prior to treatment. It could
also lead to the development of new supplemental therapies which
target the inflammatory aspects of the disease. Recent studies have
explored the possibility of using immuno-modulatory drugs such as
cyclooxygenase-2 (COX-2) inhibitors and these have been reported
to have beneficial effects on schizophrenia symptoms40,41. In addition, anti-diabetic compounds such insulin-sensitizing agents have
already been used in targeting the cognitive deficits in Alzheimers
disease patients and could equally be tested for improvement of
similar symptoms in schizophrenia42.

Inflammatory/autoimmune diseases and schizophrenia

Activation of certain immune system cells in response to an infection,
or on an ongoing low level of inflammation, may contribute to mental
illness. It is known that psychosocial stress can contribute to the onset
of autoimmune disease or affect its course by impairing the regulation of the immune reactivity43. Eaton and co-workers suggested
that the correlation between various autoimmune diseases and some
cases of schizophrenia may contribute to the disease development38.
Moreover, other studies have already linked dysfunctional immune
status to some of the clinical features of schizophrenia44,45. It has also
been hypothesised that schizophrenia shares clinical, epidemiological
and genetic characteristics with classical autoimmune diseases43,46.
A recent study carried out an analysis of the comprehensive records
of Denmarks health system, which has tracked a Danish cohort
(n = 7,704) comprised of subjects diagnosed with schizophrenia
between 1981 and 199838. The results showed that subjects who
developed any of nine different autoimmune disorders had a 1.45
fold increased risk for developing schizophrenia. The link between
inflammatory diseases, such as systemic lupus erythematosus (SLE),
and psychiatric conditions has been well-documented. For example,
cognitive dysfunctions and psychoses which are associated with
schizophrenia can also be found in patients suffering from SLE47,48.


Rahmoune H, et al. / Rev Psiq Cln. 2013;40(1):28-34

Moreover, autoimmune mechanisms may play a role in the aetiology

of schizophrenia as shown by the presence of elevated levels of auto
-antibodies in blood, cerebral spinal fluid and brain of schizophrenia
patients49. More recently, we reported that several pro-inflammatory
molecules are elevated in first onset schizophrenia patients36. Interestingly, these same molecules are also elevated in SLE patients50.
It is well established that obstetric complications and perinatal
trauma are associated with an increased chance of the offspring
later developing schizophrenia, although overall these associations
are more likely to be contributory factors. Viral infection during
pregnancy has been linked to an increased of schizophrenia in the
offspring51. Studies using a rodent model of schizophrenia have led
to the suggestion that that maternal infection during embryogenesis
contributes to microglial activation in the offspring, which may represent a contributing factor to the pathogenesis of schizophrenia52.
Also, the occurrence of schizophrenia is more common in those
born in winter to early spring, when infections are more frequent53.
Imaging studies of the brain, using positron emission tomography have also suggested that the neuropathology of schizophrenia is
associated with altered immune system function. Doorduin et al.54
used the benzodiazepine receptor ligand isoquinoline (R)-N-11Cmethyl-N-(1-methylpropyl)-1-(2-chlorophenyl) as a positron
emission tomography (PET) imaging ligand and found that neuroinflammation characterized by increased microglia cells activation is
associated with schizophrenia-related psychosis. Moreover, the mild
anti-inflammatory properties of antipsychotics are thought to be
involved in targeting the inflammatory component of schizophrenia
by acting as anti-inflammatory agents55. Moreover, inflammatory
modulating agents have been linked to damage of the vascular system
in schizophrenia56,57 and patients with schizophrenia have an average
reduction in life expectancy of approximately15 years which may be
related to the development of cardiovascular conditions58.

Modelling the inflammatory component of Schizophrenia

Although neuropsychiatric disorders are thought to be manifested
mainly as dysfunction of the central nervous system, many alterations
have also been found in peripheral tissues. This is not surprising
considering the role that the blood plays in the transport of key
regulatory factors such as hormones, nutrients and immune-related
molecules which can affect brain function. For example, various
immune system alterations have been reported in major depressive
disorder and schizophrenia59,60 including a shift from type 1 (cellular)
to type 2 (humoral) immune responses. We have conducted extensive
studies on cellular function in schizophrenia which suggests that
immune system changes are can also be seen in antigen-stimulated
T cells from patients61. We have shown that an in vitro challenge of
peripheral blood mononuclear cells (PBMC) from schizophrenia and
control subjects resulted in identification of altered signalling and
metabolic pathways62. The changes included a schizophrenia-specific
alteration in proliferation rate, glucose metabolism and an imbalance
of different T cell subpopulations. The finding of impaired glycolysis
in PBMCs isolated from first onset and drug naive schizophrenic
patients was consistent with previous studies of post-mortem brain
tissue and cerebrospinal fluid samples with regards to changes in
glucoregulation and energy metabolism63. Interestingly, these changes
were not apparent in non-stimulated cells.
PBMC express the glucose transporter 1 (GLUT1) and various
neurotransmitter receptors such as dopamine D2, 5-Hydroxytryptamine (HT) 2A, 5HT2C, 5HT1A and nicotinic acetylcholine receptors,
which are similar to those found in the brain59. This makes culture
of these cells a potentially useful model for investigating mechanisms involved in metabolic abnormalities in schizophrenia and/or
antipsychotic drug action. Interestingly, the schizophrenia-related
molecular changes appear to be normalized in PBMC in response
to treatment, and this was associated with remission of the disease64.
Other studies have shown that peripheral lymphocytes of patients
with schizophrenia had decreased expression of the receptor for
reelin, a serine protease associated with schizophrenia pathology65.

In addition, membrane fatty acid abnormalities including elevated

levels of phospholipase A2 and impaired prostaglandin signalling
have been identified and linked to the reduced niacin skin flush
response in schizophrenia patients66.
We have recently applied multiplex immunoassay in combination with mass spectrometry proteomic profiling to provide dynamic
readouts that are likely to lead to deeper molecular insights into
the cellular dysfunction associated with schizophrenia. We used a
novel ex vivo whole blood system (TruCultureTM) in the presence
or absence of an immune challenge to investigate the differential
release of molecules from blood cells at the onset of the disease67.
This cellular model more closely approximates in vivo conditions
of immune cell activity compared to isolated PBMC models. Nine
molecules showed a compromised immune status in schizophrenia
blood cells compared to those from controls and this was replicated
in an independent cohort. In silico pathway analysis showed that these
molecules had roles in endothelial cell function, inflammation, acute
phase response and fibrinolysis pathways.

Immune/metabolic dysfunction in schizophrenia

There is evidence that there are functional associations between the
peripheral and central immune systems4,68,69. For example, alterations
in the calcium-binding protein S100B associated with blood-brain
barrier function have been linked with schizophrenia at both the
peripheral and central levels70,71. A recent study has shown that
S100B secretion by human CD8+ T cells activates monocytes and
granulocytes, suggesting crosstalk between cells of the adaptive and
innate immune systems in mediating such inflammatory responses72.
Recent studies suggest that the perturbations in immune system
function seen in psychiatric disorders may result from failure to
mount an appropriate inflammatory response and could be related
to impaired metabolism61,73. This is likely to be the case as inflammatory responses consume large amounts of energy74. In support of
this, we have shown recently that glycolysis may be impaired after
stimulation of PBMC taken from schizophrenia patients75. This is also
consistent with other studies showing that drug-naive schizophrenia
subjects may have impaired insulin signalling, which regulates most
metabolic pathways in the body76,77.
The observation that metabolic disorder has been associated
with low grade systemic inflammatory conditions has led to studies
linking these two pathways. For example, the excessive adipose tissue
often associated with metabolic syndrome produces elevated levels
of proteins such as adipokines which have been implicated in the
pathogenesis of metabolic diseases including diabetes, hypertension
and cardiovascular disease78,79. In the case of psychiatric disorders,
it is still not clear whether such peripheral effects on metabolism or
on immune function are a cause or consequence of central nervous
system disturbances. The central nervous system responds to inflammatory processes through activation of the HPA axis and production of the stress hormone cortisol. Indeed, the HPA axis provides a
functional link between central and peripheral control of metabolism.
Most studies have identified an abnormal HPA axis response in
schizophrenia80, including elevated basal plasma cortisol and a blun
ted cortisol response to psychosocial stress81. Cortisol antagonises
the effects of insulin, inducing gluconeogenesis. Chronically elevated
cortisol levels may therefore lead to symptoms of metabolic syndrome
including hyperglycaemia, insulin resistance and increased visceral
fat deposition. Alterations in cortisol in schizophrenia patients have
been considered to be a confounding factor in studies of metabolic
features due to the high levels of psychosocial stress experienced by
psychiatric patients. However, abnormalities in glucose tolerance
have also been found independent of changes in cortisol levels82.
Moreover, HPA axis dysfunction may be mechanistically linked to
the balance of energy substrate distribution between the central and
peripheral systems.
One of the major contributing factors to schizophrenia comorbidities which could lead to an inflammatory response includes
an increased risk for metabolic syndrome, weight gain and type II

Rahmoune H, et al. / Rev Psiq Cln. 2013;40(1):28-34

diabetes. These effects have been attributed mainly to side effects

of atypical antipsychotic medications such as clozapine and olanzapine83. However, impaired fasting glucose tolerance has also been
reported in first onset antipsychotic-nave schizophrenia cases, suggesting that disease-inherent abnormalities in glucose metabolism
may already be present in the earliest stages of the disease77,84. Also,
effects on changes in the inflammatory response have been reported
for first onset patients26. Interestingly, not all schizophrenia subjects
develop such effects, suggesting that an empirical means of predicting
treatment responses would be a major benefit.
Recently, we carried out a system biology analysis combining a
comprehensive literature search and large in-house database on peripheral biomarkers associated with schizophrenia85. This analysis has
shown categorically that immunological disease, and inflammatory
responses are the top diseases associated with these molecular lists
and significantly associated with schizophrenia. Moreover, the top
canonical pathway analysis of schizophrenia sera proteome biomarkers studies provided further evidence for altered immunological and/
or inflammatory signalling in schizophrenia85.

Clinical need
There is now agreement that there is a fundamental lack of understanding of the biological abnormalities associated with severe mental
illnesses, which are still defined by vague symptomatic descriptions
that do not address the etiological heterogeneity of these conditions.
The available therapeutic regimes are aimed largely at relieving
symptoms and may only slow or halt disease progression at an early
stage. Thus early and accurate diagnosis is essential.
Many patients with neuropsychiatric diseases such as schizophrenia remain unrecognised or have received incorrect or late diagnoses.
The recognition rate of schizophrenia in primary care settings is less
than 50%. The main reason for this is that the current diagnosis of
schizophrenia is subjective. This is a result of the complex spectrum of
symptoms, the overlap of these symptoms with those in other mental
disorders, and the current lack of empirical markers specific for these
diseases. Moreover, less than 50% of schizophrenia patients respond
favourably to an initial treatment with antipsychotic medication86,87.
This is most likely a result of the insufficient understanding of the
underlying pathophysiology of schizophrenia to inform diagnosis or
guide treatment selection. Furthermore, traditional pharmacotherapy
for schizophrenia using blockbuster drugs usually leads to admi
nistration and switching of drugs multiple times until an adequate
response is achieved. It is perhaps not surprising that there is a low
treatment response rate and that relapse is common88.
The idea of personalized medicine approaches in psychiatric
could be realized using molecular biomarkers which target subgroups
of patients based on inflammatory, metabolic or HPA axis status. A
molecular test that recognizes such subtypes may also be used for
identifying those patients who are most likely to respond to a particular treatment89. The development of empirical immuno- or neuroendocrine markers and objective diagnostic and prognostic blood tests
for psychiatric disorders, based on an integral approach of proteomics
would be a major breakthrough in the field of schizophrenia. The discovery of novel diagnostic or therapeutically useful biomarkers involves
profiling of biological samples in search for disease related qualitative
and quantitative changes of molecules. Biomarkers which target alterations in the immune system, for example, could form the basis of novel
empirical tests for patient stratification at the onset and throughout
disease progression. This will ultimately pave the way for personalised
medicine strategies with a focus on the inflammatory component of
the disease. Nevertheless, environmental effects (seasonal illnesses)
and co-morbidities (diabetes, metabolic syndrome) associated with
schizophrenia should be considered when these strategies are applied.
Most of the omic studies conducted on peripheral and central
systems document only an association between pro-inflammatory
status and schizophrenia, and not a cause or effect. We have successfully used molecular profiling platforms to identify specific schizophrenia brain and serum signatures relating to immune function/


inflammation23,36. These and studies from other researchers have

provided unique insights into the molecular pathways underlying the
disease pathophysiology. In the case of schizophrenia, studies have
now advanced to the stage where we can distinguish schizophrenia
from control subjects with high sensitivity and specificity, and we
can also partially distinguish schizophrenia from subjects with other
neuropsychiatric disorders90. In particular, we have identified a bloodbased disease signature comprised of a refined 51-plex immunoassay
panel which has been validated by testing on a large independent
cohort of schizophrenia (n = 577) and control (n = 229) subjects. The
51 molecules are involved in inflammatory, hormonal and metabolic
pathways which are known to be affected in schizophrenia.
There is a need for clinicians to employ multiple strategies to
minimize the inflammatory risk in schizophrenia patients at all
stages of the disease. Alternative treatment strategies have also been
attempted for central nervous system disorders associated with metabolic perturbations91. For example, peroxisome proliferator-activated
receptor gamma (PPAR-g) agonists with anti-inflammatory and antidiabetic properties have been used to treat behavioural symptoms
in autism92 and cognitive deficits associated with neurodegenerative
disorders93. In addition, this approach has also been employed as an
anti-inflammatory and neuroprotective agent94. This includes the use
of anti-diabetics such as dipeptidyl peptidase IV (DPP-IV) inhibitors
or PPAR-g agonists95.
The inflammatory component of the disease could be targeted by
existing or novel anti-inflammatory agents as add on or stand-alone
therapies to alleviate the symptoms or contribute to schizophrenia
treatment. Recent studies have already tested the potential of using
anti-inflammatory agents to target the inflammatory component
of schizophrenia and improve the clinical rating96. More, recently
acetylsalicylic acid given as adjuvant therapy to regular antipsychotic
treatment was used to reduce the symptoms associated with schizophrenia spectrum disorders97. Such a strategy has shown that these
anti-inflammatory agents were beneficial in treating or managing
mental disorders with schizophrenia as the reduction in symptoms
were more pronounced in those subjects with more pronounced
alterations in immune function97. This could be of major importance
since recent studies have found that alterations in the inflammatory
response may contribute to early development of schizophrenia27
with the possibility that certain infectious agents can contribute to
the disease onset98.
A proof of concept study has already been conducted in humans
and cox-2 inhibitors have been tested as an alternative treatment for
schizophrenia11. Similar strategies could also be applied in future
therapeutics by using existing humanised monoclonal therapy or
biopharmaceuticals on schizophrenia patients. It has already been
found that targeting amyloid peptide oligomers by passive immunization with a conformation selective monoclonal antibody improves
learning and memory in a mouse model of Alzheimers disease99. Also,
an IL-6 receptor-inhibiting monoclonal antibody, a tumour necrosis
factor alpha (TNF-) antibody (Infliximab) and etanercept (a soluble
TNF-receptor-Fc fusion protein) are already in use in the clinic for
treatment of rheumatoid arthritis patients100. These could be tested on
patients suffering from mental disorders such as schizophrenia, however one drawback of this strategy would be the occurrence potential
side effects such as increased rates of infection101. This could potentially
contribute to symptom exacerbation rather than alleviation. Therefore,
well designed clinical trials are essential for future research.
A successful outcome of biomarker-based studies should assist
clinicians in stratifying schizophrenia patients for selection of the
most appropriate therapeutic regimens. This will reduce incidence
of inflammatory effects, improve patient compliance and increase
the proportion of patients that respond favourably to therapy with
regards to psychopathology.

It is has been established that central and peripheral pro-inflammatory status is a significant component of schizophrenia. As ongoing


Rahmoune H, et al. / Rev Psiq Cln. 2013;40(1):28-34

and future studies aim to investigate the relationship between the

cause and effect of the inflammatory component of schizophrenia,
advances in molecular profiling platforms have given us the possibility to understand the disease at a more fundamental level. This
should pave the way for designing biomarker-based tests for stratification of the patients based on their molecular profile at different
stages of the disease. Targeting the inflammatory component of a
multi-factorial disease such as schizophrenia requires well-designed
preclinical and clinical studies to correlate molecular data with clinical ratings. This comprehensive strategy (Figure 1) should enable us
to understand schizophrenia aetiology and, more precisely, the role
of the inflammatory component in this disease. It will also allow us
to develop a flexible and progressive personalised medicine strategy
based on patient stratification from the onset to late stage of the
disease. The proposed paradigm change targeting the inflammatory
component of schizophrenia at different stages of the disease might
lead to alleviation of some symptoms, preventing the disease onset
and/or slowing progression. Further studies in this area could also
lead to the development of a novel target discovery strategy based on
patient stratification at the molecular level. More importantly, there
are conflicting reports in regards to the nature of pro-inflammatory
agents as well as their directional changes that are associated with
schizophrenia85. As the immune system is ever changeable/adaptable,
a personalised medicine strategy based on targeting the inflammatory component of schizophrenia should be tailored throughout the
disease progression to suit the patient inflammatory status.
External insults
drug abuse/stress

Genetic pre-disposition
Neuro-developmental defect




inflammatory component


Aid diagnostic

Blood/brain molecular
(Omics and clinical rating)

Novel therapy

Adjuvant therapy

Figure 1. Schematic diagram representing personalised medicine strategy

based on targeting the inflammatory component of schizophrenia.



This research was supported by the Stanley Medical Research Institute
(SMRI), the European Union FP7 SchizDX research programme
(grant reference 223427) and the NEWMEDS Innovative Medicines

1. Robins E, Guze SB. Establishment of diagnostic validity in psychiatric illness: its application to schizophrenia. Am J Psychiatry. 1970;126(7):983-7.
2. Kinney DK, Hintz K, Shearer EM, Barch DH, Riffin C, Whitley K, et
al. A unifying hypothesis of schizophrenia: abnormal immune system



development may help explain roles of prenatal hazards, post-pubertal

onset, stress, genes, climate, infections, and brain dysfunction. Med
Hypotheses. 2010;74(3):555-63.
Muller N, Schwarz MJ. Immune system and schizophrenia. Curr Immunol Rev. 2010;6(3):213-20.
Steinman L. Elaborate interactions between the immune and nervous
systems. Nat Immunol. 2004;5(6):575-81.
Severance EG, Lin J, Sampson HA, Gimenez G, Dickerson FB, Halling M,
et al. Dietary antigens, epitope recognition, and immune complex formation in recent onset psychosis and long-term schizophrenia. Schizophr
Res. 2010;126(1-3):43-50.
Tiwari AK, Zai CC, Mller DJ, Kennedy JL. Genetics in schizophrenia: where are we and what next? Dialogues Clin Neurosci.
Sawa A, Snyder SH. Schizophrenia: diverse approaches to a complex
disease. Science. 2002;296(5568):692-5.
Badner JA, Gershon ES. Meta-analysis of whole-genome linkage scans
of bipolar disorder and schizophrenia. Mol Psychiatry. 2002;7(4):405-11.
Hnninen K, Katila H, Saarela M, Rontu R, Mattila KM, Fan M, et al.
Interleukin-1 beta gene polymorphism and its interactions with neuregulin-1 gene polymorphism are associated with schizophrenia. Eur
Arch Psychiatry Clin Neurosci. 2008;258(1):10-5.
Tosato S, Dazzan P, Collier D. Association between the neuregulin 1 gene
and schizophrenia: a systematic review. Schizophr Bull. 2005;31(3):613-7.
Muller N, Myint AM, Schwarz MJ. The impact of neuroimmune dysregulation on neuroprotection and neurotoxicity in psychiatric disorders:
relation to drug treatment. Dialogues Clin Neurosci. 2009;11(3):319-32.
Soderlund J, Schroder J, Nordin C, Samuelsson M, Walther-Jallow L,
Karlsson H, et al. Activation of brain interleukin-1beta in schizophrenia.
Mol Psychiatry. 2009;14(12):1069-71.
Merrill JE. Tumor necrosis factor alpha, interleukin 1 and related cytokines in brain development: normal and pathological. Dev Neurosci.
Mehler MF, Kessler JA. Hematolymphopoietic and inflammatory cytokines in neural development. Trends Neurosci. 1997;20(8):357-65.
Meyer U, Feldon J, Yee BK. A review of the fetal brain cytokine imba
lance hypothesis of schizophrenia. Schizophr Bull. 2009;35(5):959-72.
Paterson GJ, Ohashi Y, Reynolds GP, Pratt JA, Morris BJ. Selective increases in the cytokine, TNFalpha, in the prefrontal cortex of PCP-treated
rats and human schizophrenic subjects: influence of antipsychotic drugs.
J Psychopharmacol. 2006;20(5):636-42.
Saetre P, Emilsson L, Axelsson E, Kreuger J, Lindholm E, Jazin E.
Inflammation-related genes up-regulated in schizophrenia brains. BMC
Psychiatry. 2007;7:46.
Altar CA, Vawter MP, Ginsberg SD. Target identification for CNS
diseases by transcriptional profiling. Neuropsychopharmacology.
Schmitt A, Leonardi-Essmann F, Durrenberger PF, Parlapani E, Schneider-Axmann T, Spanagel R, et al. Regulation of immune-modulatory
genes in left superior temporal cortex of schizophrenia patients: a genome-wide microarray study. World J Biol Psychiatry. 2011;12(3): 201-15.
Sullivan PF, Fan C, Perou CM. Evaluating the comparability of gene expression in blood and brain. Am J Med Genet B Neuropsychiatr Genet.
Rothermundt M, Arolt V, Bayer TA. Review of immunological and
immunopathological findings in schizophrenia. Brain Behav Immun.
Arion D, Unger T, Lewis DA, Levitt P, Mirnics K. Molecular evidence
for increased expression of genes related to immune and chaperone
function in the prefrontal cortex in schizophrenia. Biol Psychiatry.
Martins-de-Souza D, Gattaz WF, Schmitt A, Rewerts C, Maccarrone
G, Dias-Neto E, et al. Prefrontal cortex shotgun proteome analysis
reveals altered calcium homeostasis and immune system imbalance in
schizophrenia. Eur Arch Psychiatry Clin Neurosci. 2009;259(3):151-63.
Sperner-Unterweger B. [Biological hypotheses of schizophrenia: possible influences of immunology and endocrinology]. Fortschr Neurol
Psychiatr. 2005;73(Suppl 1):S38-43.
Lyson K, McCann SM. The effect of interleukin-6 on pituitary hormone
release in vivo and in vitro. Neuroendocrinology. 1991;54(3):262-6.
Van Berckel BN, Bossong MG, Boellaard R, Kloet R, Schuitemaker A,
Caspers E, et al. Microglia activation in recent-onset schizophrenia: a

Rahmoune H, et al. / Rev Psiq Cln. 2013;40(1):28-34





quantitative (R)-[11C]PK11195 positron emission tomography study.

Biol Psychiatry. 2008;64(9):820-2.
Yolken RH, Dickerson FB, Fuller Torrey E. Toxoplasma and schizophrenia. Parasite Immunol. 2009;31(11):706-15.
Bitanihirwe BK, Woo TU. Oxidative stress in schizophrenia: an integrated
approach. Neurosci Biobehav Rev. 2011;35(3):878-93.
Herberth M, Schwarz E, Bahn S. Problems and promise of immunological
factors as biomarkers for schizophrenia. Biomark Med. 2008,2(4):385-95.
Miller BJ, Buckley P, Seabolt W, Mellor A, Kirkpatrick B. Meta-analysis
of cytokine alterations in schizophrenia: clinical status and antipsychotic
effects. Biol Psychiatry. 2011;70(7):663-71.
Reale M, Patruno A, De Lutiis MA, Pesce M, Felaco M, Di Giannantonio
M, et al. Dysregulation of chemo-cytokine production in schizophrenic
patients versus healthy controls. BMC Neurosci. 2011;12:13.
Drexhage RC, Knijff EM, Padmos RC, Heul-Nieuwenhuijzen L, Beumer
W, Versnel MA, et al. The mononuclear phagocyte system and its cytokine
inflammatory networks in schizophrenia and bipolar disorder. Expert
Rev Neurother. 2010;10(1):59-76.
Cazzullo CL, Sacchetti E, Galluzzo A, Panariello A, Colombo F, Zagliani
A, et al. Cytokine profiles in drug-naive schizophrenic patients. Schizophr
Res. 2001;47(2-3):293-8.
Kim YK, Myint AM, Lee BH, Han CS, Lee HJ, Kim DJ, et al. Th1, Th2 and
Th3 cytokine alteration in schizophrenia. Prog Neuropsychopharmacol
Biol Psychiatry. 2004;28(7):1129-34.
Smith RS. A comprehensive macrophage-T-lymphocyte theory of schizophrenia. Med Hypotheses. 1992;39(3):248-57.
Schwarz E, Guest PC, Rahmoune H, Harris LW, Wang L, Leweke FM,
et al. Identification of a biological signature for schizophrenia in serum.
Mol Psychiatry. 2011;17(5):494-502. doi: 10.1038/mp.2011.42. Epub
2011 Apr 12.
Fessel WJ, Solomon GF. Psychosis and systemic lupus erythematosus:
a review of the literature and case reports. Calif Med. 1960;92:266-70.
Eaton WW, Byrne M, Ewald H, Mors O, Chen CY, Agerbo E, et al. Association of schizophrenia and autoimmune diseases: linkage of Danish
national registers. Am J Psychiatry. 2006;163(3):521-8.
Volp AC, Alfenas Rde C, Costa NM, Minim VP, Stringueta PC, Bressan
J. [Inflammation biomarkers capacity in predicting the metabolic syndrome]. Arq Bras Endocrinol Metabol. 2008;52(3):537-49.
Mller N, Riedel M, Schwarz MJ. Clinical effects of COX-2 inhibitors
on cognition in schizophrenia. Eur Arch Psychiatry Clin Neurosci.
Akhondzadeh S, Tabatabaee M, Amini H, Ahmadi Abhari SA, Abbasi
SH, Behnam B. Celecoxib as adjunctive therapy in schizophrenia: a
double-blind, randomized and placebo-controlled trial. Schizophr Res.
Sato T, Hanyu H, Hirao K, Kanetaka H, Sakurai H, Iwamoto T. Efficacy of
PPAR-gamma agonist pioglitazone in mild Alzheimer disease. Neurobiol
Aging. 2011;32(9):1626-33.
Wright P, Sham PC, Gilvarry CM, Jones PB, Cannon M, Sharma T, et
al. Autoimmune diseases in the pedigrees of schizophrenic and control
subjects. Schizophr Res. 1996;20(3):261-7.
Jones AL, Mowry BJ, Pender MP, Greer JM. Immune dysregulation and
self-reactivity in schizophrenia: do some cases of schizophrenia have an
autoimmune basis? Immunol Cell Biol. 2005;83(1):9-17.
Strous RD, Shoenfeld Y. Schizophrenia, autoimmunity and immune
system dysregulation: a comprehensive model updated and revisited. J
Autoimmun. 2006;27(2):71-80.
Pearce BD. Schizophrenia and viral infection during neurodevelopment:
a focus on mechanisms. Mol Psychiatry. 2001;6(6):634-46.
Stojanovich L, Zandman-Goddard G, Pavlovich S, Sikanich N. Psychia
tric manifestations in systemic lupus erythematosus. Autoimmun Rev.
Pego-Reigosa JM, Isenberg DA. Psychosis due to systemic lupus erythematosus: characteristics and long-term outcome of this rare manifestation
of the disease. Rheumatology (Oxford). 2008;47(10):1498-502.
Sirota P, Firer MA, Schild K, Tanay A, Elizur A, Meytes D, et al. Autoantibodies to DNA in multicase families with schizophrenia. Biol Psychiatry.
Matei, I, Matei L. Cytokine patterns and pathogenicity in autoimmune
diseases. Rom J Intern Med. 2002;40(1-4):27-41.


51. Brown AS. The risk for schizophrenia from childhood and adult infections. Am J Psychiatry. 2008;165(1):7-10.
52. Juckel G, Manitz MP, Brne M, Friebe A, Heneka MT, Wolf RJ. Microglial
activation in a neuroinflammational animal model of schizophrenia: a
pilot study. Schizophr Res. 2011;131(1-3):96-100.
53. Torrey EF, Miller J, Rawlings R, Yolken RH. Seasonality of births in
schizophrenia and bipolar disorder: a review of the literature. Schizophr
Res. 1997;28(1):1-38.
54. Doorduin J, De Vries EF, Willemsen AT, De Groot JC, Dierckx RA, Klein
HC. Neuroinflammation in schizophrenia-related psychosis: a PET study.
J Nucl Med. 2009;50(11):1801-7.
55. Kato TA, Monji A, Mizoguchi Y, Hashioka S, Horikawa H, Seki Y, et al.
Anti-inflammatory properties of antipsychotics via microglia modulations: are antipsychotics a fire extinguisher in the brain of schizophrenia?
Mini Rev Med Chem. 2011;11(7):565-74.
56. Hanson DR, Gottesman II. Theories of schizophrenia: a genetic-inflammatory-vascular synthesis. BMC Med Genet. 2005;6:7.
57. Harris LW, Wayland M, Lan L, Ryan M, Giger T, Lockstone H, et al. The
cerebral microvasculature in schizophrenia: a laser capture microdissection study. PLoS One. 2008;3(12):e3964.
58. Koponen H, Alarisnen A, Saari K, Pelkonen O, Huikuri H, Raatikainen
MJ, et al. Schizophrenia and sudden cardiac death: a review. Nord J
Psychiatry. 2008;62(5):342-5.
59. Theodoropoulou S, Spanakos G, Baxevanis CN, Economou M, Gritzapis AD, Papamichail MP, et al. Cytokine serum levels, autologous
mixed lymphocyte reaction and surface marker analysis in never medicated and chronically medicated schizophrenic patients. Schizophr Res.
60. Riedel M, Spellmann I, Schwarz MJ, Strassnig M, Sikorski C, Mller HJ,
et al. Decreased T cellular immune response in schizophrenic patients.
J Psychiatr Res. 2007;41(1-2):3-7.
61. Craddock RM, Lockstone HE, Rider DA, Wayland MT, Harris LJ, Mc
Kenna PJ, et al. Altered T-cell function in schizophrenia: a cellular model
to investigate molecular disease mechanisms. PLoS One. 2007;2(8):e692.
62. Herberth M, Koethe D, Cheng TM, Krzyszton ND, Schoeffmann S, Guest
PC, et al. Impaired glycolytic response in peripheral blood mononuclear
cells of first-onset antipsychotic-naive schizophrenia patients. Mol Psychiatry. 2011;16(8):848-59.
63. Martins-de-Souza D, Harris LW, Guest PC, Bahn S. The role of energy
metabolism dysfunction and oxidative stress in schizophrenia revealed
by proteomics. Antioxid Redox Signal. 2011;15(7):2067-79.
64. Kuzman MR, Medved V, Terzic J, Krainc D. Genome-wide expression
analysis of peripheral blood identifies candidate biomarkers for schizophrenia. J Psychiatr Res. 2009;43(13):1073-7.
65. Suzuki K, Nakamura K, Iwata Y, Sekine Y, Kawai M, Sugihara G, et al.
Decreased expression of reelin receptor VLDLR in peripheral lymphocytes of drug-naive schizophrenic patients. Schizophr Res. 2008;98(13):148-56.
66. Messamore E, Hoffman WF, Janowsky A. The niacin skin flush abnormality in schizophrenia: a quantitative dose-response study. Schizophr
Res. 2003;62(3):251-8.
67. Herberth M, et al. Identification of a molecular profile associated with
immune status in first onset schizophrenia patients. Clin Schizophr Relat
Psychoses. 2011. In press.
68. DeLisi LE, Crow TJ. Is schizophrenia a viral or immunologic disorder?
Psychiatr Clin North Am. 1986;9(1):115-32.
69. Ganguli R, Brar JS, Rabin BS. Immune abnormalities in schizophrenia: evidence for the autoimmune hypothesis. Harv Rev Psychiatry.
70. Steiner J, Bielau H, Bernstein HG, Bogerts B, Wunderlich MT. Increased
cerebrospinal fluid and serum levels of S100B in first-onset schizophrenia
are not related to a degenerative release of glial fibrillar acidic protein,
myelin basic protein and neurone-specific enolase from glia or neurones.
J Neurol Neurosurg Psychiatry. 2006;77(11):1284-7.
71. Steiner J, Bernstein HG, Bielau H, Farkas N, Winter J, Dobrowolny H,
et al. S100B-immunopositive glia is elevated in paranoid as compared
to residual schizophrenia: a morphometric study. J Psychiatr Res.
72. Steiner J, Marquardt N, Pauls I, Schiltz K, Rahmoune H, Bahn S, et al.
Human CD8(+) T cells and NK cells express and secrete S100B upon
stimulation. Brain Behav Immun. 2011;25(6):1233-41.


Rahmoune H, et al. / Rev Psiq Cln. 2013;40(1):28-34

73. Nilsson BM, Hultman CM, Wiesel FA. Niacin skin-flush response
and electrodermal activity in patients with schizophrenia and healthy
controls. Prostaglandins Leukot Essent Fatty Acids. 2006;74(5):339-46.
74. Peters A. The energy request of inflammation. Endocrinology.
75. Herberth M, Koethe D, Levin Y, Schwarz E, Krzyszton ND, Schoeffmann
S, et al. Peripheral profiling analysis for bipolar disorder reveals markers
associated with reduced cell survival. Proteomics. 2011;11(1):94-105.
76. Ryan MC, Collins P, Thakore JH. Impaired fasting glucose tolerance in
first-episode, drug-naive patients with schizophrenia. Am J Psychiatry.
77. Guest PC, Schwarz E, Krishnamurthy D, Harris LW, Leweke FM,
Rothermundt M, et al. Altered levels of circulating insulin and other
neuroendocrine hormones associated with the onset of schizophrenia.
Psychoneuroendocrinology. 2011;36(7):1092-6.
78. Mathieu P, Pibarot P, Desprs JP. Metabolic syndrome: the danger signal
in atherosclerosis. Vasc Health Risk Manag. 2006;2(3):285-302.
79. Karalis KP, Giannogonas P, Kodela E, Koutmani Y, Zoumakis M, Teli T.
Mechanisms of obesity and related pathology: linking immune responses
to metabolic stress. FEBS J. 2009;276(20):5747-54.
80. Corcoran C, Walker E, Huot R, Mittal V, Tessner K, Kestler L, et al. The
stress cascade and schizophrenia: etiology and onset. Schizophr Bull.
81. Brenner K, Liu A, Laplante DP, Lupien S, Pruessner JC, Ciampi A, et al.
Cortisol response to a psychosocial stressor in schizophrenia: blunted,
delayed, or normal? Psychoneuroendocrinology. 2009;34(6):859-68.
82. Fernandez-Egea E, Bernardo M, Donner T, Conget I, Parellada E, Justicia
A, et al. Metabolic profile of antipsychotic-naive individuals with nonaffective psychosis. Br J Psychiatry. 2009;194(5):434-8.
83. Pramyothin P, Khaodhiar L. Metabolic syndrome with the atypical
antipsychotics. Curr Opin Endocrinol Diabetes Obes. 2010;17(5):460-6.
84. Spelman LM, Walsh PI, Sharifi N, Collins P, Thakore JH. Impaired glucose
tolerance in first-episode drug-naive patients with schizophrenia. Diabet
Med. 2007;24(5):481-5.
85. Chan MK, Guest PC, Levin Y, Umrania Y, Schwarz E, Bahn S, et al.
Converging evidence or blood-based biomarkers for schizophrenia: an
update. Int Rev Neurobiol. 2011;101:95-144.
86. Buckley PF, Friedman L, Krowinski AC, Eaton Y, Tronetti M,
Miller DD. Clinical and biochemical correlates of high-dose clozapine therapy for treatment-refractory schizophrenia. Schizophr
Res. 200149(1-2):225-7.
87. Chakos M, Lieberman J, Hoffman E, Bradford D, Sheitman B. Effectiveness of second-generation antipsychotics in patients with treatment-

resistant schizophrenia: a review and meta-analysis of randomized trials.

Am J Psychiatry. 2001;158(4):518-26.
88. McIlwain ME, Harrison J, Wheeler AJ, Russell BR. Pharmacotherapy
for treatment-resistant schizophrenia. Neuropsychiatr Dis Treat.
89. Madaan V, Bestha DP, Kolli VB. Biological markers in schizophrenia: an
update. Drugs Today (Barc). 2010;46(9):661-9.
90. Schwarz E, Izmailov R, Spain M, Barnes A, Mapes JP, Guest PC, et al.
Validation of a blood-based laboratory test to aid in the confirmation of
a diagnosis of schizophrenia. Biomark Insights. 2011;5:39-47.
91. Dello Russo C, Gavrilyuk V, Weinberg G, Almeida A, Bolanos JP, Palmer
J, et al. Peroxisome proliferator-activated receptor gamma thiazolidine
dione agonists increase glucose metabolism in astrocytes. J Biol Chem.
92. Williams AJ, Wei HH, Dave JR, Tortella FC. Acute and delayed neuroinflammatory response following experimental penetrating ballistic brain
injury in the rat. J Neuroinflammation. 2007;4:17.
93. Landreth G. PPARgamma agonists as new therapeutic agents for the
treatment of Alzheimers disease. Exp Neurol. 2006;199(2):245-8.
94. Kapadia R, Yi JH, Vemuganti R. Mechanisms of anti-inflammatory
and neuroprotective actions of PPAR-gamma agonists. Front Biosci.
95. Edlinger M, Ebenbichler C, Rettenbacher M, Fleischhacker WW. Treatment of antipsychotic-associated hyperglycemia with pioglitazone: a case
series. J Clin Psychopharmacol. 2007;27(4):403-4.
96. Berthold-Losleben M, Heitmann S, Himmerich H. Anti-inflammatory
drugs in psychiatry. Inflamm Allergy Drug Targets. 2009;8(4):266-76.
97. Laan W, Grobbee DE, Selten JP, Heijnen CJ, Kahn RS, Burger H. Adjuvant
aspirin therapy reduces symptoms of schizophrenia spectrum disorders:
results from a randomized, double-blind, placebo-controlled trial. J Clin
Psychiatry. 2010;71(5):520-7.
98. Torrey EF, Yolken RH. Schizophrenia and toxoplasmosis. Schizophr
Bull. 2007;33(3):727-8.
99. Lee EB, Leng LZ, Zhang B, Kwong L, Trojanowski JQ, Abel T, et al. Targeting amyloid-beta peptide (Abeta) oligomers by passive immunization
with a conformation-selective monoclonal antibody improves learning
and memory in Abeta precursor protein (APP) transgenic mice. J Biol
Chem. 2006;281(7):4292-9.
100. Feldmann M, Maini RN. Anti-TNF alpha therapy of rheumatoid arthritis:
what have we learned? Annu Rev Immunol. 2001;19:163-96.
101. Hansel TT, Kropshofer H, Singer T, Mitchell JA, George AJ. The
safety and side effects of monoclonal antibodies. Nat Rev Drug Discov.